Abstract Details

Title Cdk5 inhibition in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis suppresses neurodegeneration and extends survival.

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P1 - Poster Session 1 (8:00 AM-9:00 AM)

Poster/Presentation
Number 7-001

Objective To investigate the effects of cyclin-dependent kinase 5 (Cdk5) inhibition on transgenic mice carrying superoxide dismutase 1 (SOD1^G93A) mutation in the perspective of neurodegeneration.

Background Deregulated Cdk5 activity is closely correlated with hyperphosphorylated tau, a common pathology found in neurodegenerative disease. Postmortem study revealed increased Cdk5 immunoreactivity in amyotrophic lateral sclerosis (ALS), however, Cdk5-silencing impacts on ALS are unheralded. Therefore, the effects of Cdk5 inhibition on ALS-model mice and neurons were investigated in this study.

Design/Methods

For in vitro study, effects of Cdk5 inhibition on motor neuron cell lines with wild type SOD1 or mutant SOD1^G93A and primary neuronal cultures from SOD1^G93A mice or wild type mice were evaluated with respect to expression of proteins involved in tau pathology, neuroinflammation, apoptosis, and neuritic outgrowth. For in vivo study, SOD1^G93A mice and wild type mice were intrathecally injected with AAV9-scramble(SCR)-shRNA or AAV9-Cdk5-shRNA at the age of 5 weeks. Motor function and longevity were assessed and tissues were collected from 90-day-old or 120-day-old mice.

Results The neurons with SOD1^G93A showed increased phosphorylated tau, attenuated neuritic growth, mislocalization of SOD1, enhanced neuroinflammation and apoptosis, all of which were reverted by Cdk5 inhibition. The SOD1^G93A mice treated with AAV9-Cdk5-shRNA had significantly delayed disease onset (p < 0.001), delayed rotarod failure (p = 0.032), and prolonged survival (p = 0.007) compared to those treated with AAV9-SCR-shRNA. The brain and spinal cord of the SOD1^G93A mice injected with AAV9-Cdk5-shRNA exhibited suppressed tau pathology, neuroinflammation, apoptosis and increased number of motor neurons compared to those of the SOD1^G93A mice injected with AAV9-SCR-shRNA.

Conclusions

Cdk5 inhibition could be a major mechanism for a new therapeutic for ALS.

Authors/Disclosures
Ahwon Kim, MD (Seoul National University Hospital) PRESENTER	Dr. Kim has nothing to disclose.
	No disclosure on file
	No disclosure on file

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